2-carboxamido penicillin derivatives

ABSTRACT

Phenoxymethyl, Alpha -aminobenzyl and phenylimidazolidinyl penicillin derivatives are prepared. The compounds are effective antibacterials with a substantial spectrum of activity and good duration of action.

United States Patent Sellstedt et al.

[451 Sept. 19, 1972 2-CARBOXAMIDO PENICILLIN DERIVATIVES [72] Inventors:John H. Sellstedt, 266 lven Ave., St. Davids, Pa. 19087; Milton Wolf,

1 100 Westchcater Pike, West Chester, Pa. 19380 [22] Filed: Aug. 31,1970 [21] Appl. No.: 68,527

[52] US. Cl ..260/239.1, 424/271 [51] Int. Cl. ..C07d 99/16 [58] Fieldof Search ..260/239.1

[56] References Cited UNITED STATES PATENTS 3,383,383 5/1968 Gapp et al."260/2391 tor Bellino and Robert Wiser [57] ABSTRACT Phenoxymethyl,a-aminobenzyl and phenylimidazolidinyl penicillin derivatives areprepared. The compounds are effective antibacterials with a substantialspectrum of activity and good duration of action.

7 Claims, No Drawings Z-CARBOXAMIDO PENICILLIN DERIVATIVES Thisinvention relates to new synthetic penicillins and more particularly tocarboxamido penicillin derivatives having an extended period ofeffective antibiotic activity.

Antibiotics prepared for medicinal use are generally put into a formwhere they are soluble in body fluids. Insofar as penicillins areconcerned, their solubility in body fluids or in a largely aqueoussystem have required forming a salt of such penicillins whose solubility in water varied in accordance with the type of base used to reactwith the penicillin. For example, an alkali metal salt of a penicillinis known to be highly water soluble but its antibiotic effectiveness isrelatively short. On the other hand, using an organic base andparticularly selected alkylenediamine bases will form acid-additionsalts with penicillins that are very sparingly soluble in water andcharacterized by a long duration of action. The latter characteristic,however, has the limiting effect of yielding very low blood levels ofpenicillin. The present invention seeks to improve blood levels and yetretain a reasonably extended duration of antibiotic activity.

The compounds of the invention found to achieve the aforesaid desirablecharacteristics may be represented by the structural formula designatedas follows:

In the above illustration, X is intended to represent any of the knownpenicillin radicals attaching to the 6- position of the penicillinmoiety but preferable either an acetamido radical particularly aphenoxyacetamido or 2-amino-2-phenyl-acetamido or a condensed" acetamidogroup such as a substituted phenylimidazolidinyl radical, e.g., the6-position radical of hetacillin.

The radicals or symbols R and R are intended to separately represent alower alkyl of one to four carbon atoms, a haloalkyl, e.g.,trifluoromethyl, or aryl, preferably a monocyclic aryl such as phenyl,methoxyphenyl, or aralkyl, preferably benzyl and one of R and R but notboth may be hydrogen. Additionally, when taken together, R and Rcombined with the amido moiety and represented by may stand for eitherin which n is a whole number from 1 to 4; or the radicals:

Reverting to the imidazolidinyl radical previously mentioned, this isillustrated with greater specificity by the formula:

@ R, Rs

in which the radicals R and R separately represent hydrogen or loweralkyl of one to four carbon atoms, and when taken together they mayrepresent (Cl--l,), 2)2' 2)2; or

where n is a whole number 3, 4, 5, 6, or 7, and where R, is a loweralkyl of one to four carbon atoms or aryl, preferably phenyl or benzoyl.

The compounds of the invention are prepared by starting with a selectedpenicillanic acid, preferably one of those described in Behrens et al.,U.S. Pat. No. 2,562,410 or Brandt et al., U.S. Pat. No. 2,756,226; or inDoyle et al., U.S. Pat. No. 2,985,648 or Grant et al., U.S. Pat. No.3,144,445; or in Johnson et al., U.S. Pat. No. 3,198,804 or Alburn etal., U.S. Pat. No. 3,351,587. The selected penicillanic acid, either assuch (I) or in the form of its alkali metal or amine salt, in a solventsuch as methylene chloride is reacted with an iminochloride (ll), underambient temperatures, a reaction in the form of a rearrangement takesplace to form the final desired compound (Ill). The reaction steps arebest illustrated by the reaction scheme as shown:

When the iminochl oride II is one having joined R and R radicals asdescribed above, this type of reactant would fall within one of theillustrated structures shown herein:

In formula Ila, the symbol n would represent the integers previouslyassigned, namely, 1 to 4. All of the reactants are either knowncompounds or, with respect to the iminochlorides, if these are noteasily available, they may be prepared by known means as taught by vonBraun and Pinkemelle in Ber. 67, 1218 (1934), Huisgen, Sauer and Seidel,Ber. 93, 2885 1960), or by H. Ulrich in The Chemistry of lmidoylHalides, Plenum Press, New York, 1968. In general, the preparationmerely involves the chlorination of an N- substituted amide with thionylchloride.

The compounds of the invention have been found to be effective againstgram-positive and gram-negative test organisms at an inhibitoryconcentration below 1,000 ugJml. using the well-known and scientificallyaccepted agar serial dilution technique. Typical test organisms of thegram-positive type are, for example, Bacillus subtilis andStaphylococcus aureus; tests organisms of the gram-negative type are,for example, En-

. fields of comparative pharmacology and microbiology.

The following examples are provided for illustrative purposes inpreparing compounds of the invention by the best mode contemplatedherein.

EXAMPLE 1 N-Benzoyl-3 ,3-dimethyl-7-oxo-6-( 2-phenoxyacetamido)-N-phenyl-4-thia l -azabicyclo 3 .2.0 ]heptane-2-carboxamide3,3-Dimethyl-7-oxo-6-(2-phenoxyacetamido)-4-thia-1-azabicyclo[3.2.0]heptane-Z-carboxylic acid (8.75 g., 0.025 mole)is added to anhydrous methylene chloride (200 ml.) followed bytriethylamine (2.53 g., 0.025 mole), giving asolution. Then solidN-phenylbenzimidoyl chloride (5.4 g., 0.025 mole) is added to thestirred solution, and theresulting solution-is kept at room temperaturefor 2 hours. The solution is then washed once with cold water, once withcold 0.13 M/pH 7.4/(K HPO /KH PO buffer, and dried through sodiumsulfate. The filtrate is dried over magnesium sulfate, and thenconcentrated at 40 under vacuum, giving a foam. The foam is dissolved inanhydrous ether (==150 ml.) and the solution is filtered into a literErlenmeyer flask. The solution is stirred in an ice bath, and pentane(=600 ml.) is added all at once, giving a solid. The mixture is stirredand the solid is rubbed with a glass rod for about one-half hour untilthe solid becomes more crystalline. The mixture is filtered, giving awhite solid (6.5 g., 49 percent), m.p. (80 soften) 95l00 (uncorr.).

Analysis Calcd. for C H N O S:

C, 65.77; H, 5.14; N, 7.93. Found: C, 65.82; H, 5.38; N, 7.89.

EXAMPLE 2 N-Benzoyl-N,3 ,3-trimethyl-7-oxo-6-(Z-phenoxyacetamido)-4-thia-1-azabicyclo[3.2.0lheptane-2-carboxamide3,3-Dimethyl-7-oxo-6-(2-phenoxyacetamido)-4- thial -azabicyclo[ 3 .2.0heptane-2-carboxylic acid (3.51 g., 0.01 mole) is added to anhydrousmethylene chloride ml.) followed by triethylamine (1.01 g., 0.01 mole),giving a solution. Then N-methylbenzimidoyl chloride (1.54 g., 0.01mole)is added all at once, and the solution is reacted and worked-up ina manner similar to Example 1, giving a white solid (2.5 g., 53percent), m.p. 91-93 (uncorr.

Analysis Calcd. for C H, N O S:

C, 61.65; H, 5.39; N, 8.99. Found: C, 62.63; H, 5.74; N, 8.28.

EXAMPLE 3 6-(D(-)-2-Amino-2-phenylacetamido)-N-benzoyl-3,3-dimethyl-7-oxo-N-phenyl-4-thia-1-azabicyclo[ 3.2.0]heptane-2-carboxamideTriethylamine (1.01 g., 0.01 mole) is added to a mixture of6-(D-(-)-2-amino-Z-phenylacetamido)-3,3- dimethyl-7-oxo-4-thia-1-azabicyc1o[3.2.0]heptane-2- carboxylic acid (3.49 g., 0.01 mole) andmethylene chloride (100 ml.) and the mixture is stirred threefourthshour at room temperature. Then solid N-phenylbenzimidoyl chloride (2.16g., 0.01 mole) is added all at once, and the mixture is stirred 2 hoursat room temperature. An insoluble solid is filtered off, and thefiltrate is washed twice with cold water, twice with cold 0.13 M/pH7.4/(K HPO /KH POJ buffer, and dried through sodium sulfate. Theresulting filtrate is dried over magnesium sulfate, and thenconcentrated at 40 under vacuum, giving a foam (2.3 g., 44 percent). Thefoam is dissolved in a minimum amount of methylene chloride (-10 ml.)and anhydrous ether (=30 ml.) is added to the cloud point. The solutionis filtered and the filtrate is stirred in a 250 ml. Erlenmeyer flask inan ice bath. Then pentane (100 ml.) is added all at once, giving a whitesolid. The .solid is stirred for =36 hour, and the mixture is filteredgiving a white solid (1.3 g., 25 percent), m.p. ll9-l46 (uncorr.).

Analysis Calcdfor C29H28N4O4S:

C, 65.89; H, 5.34; N, 10.60. Found: C, 68.04; H, 4.74; N, 9.76.

EXAMPLE 4 6-(D-(-)-2-Amino-2-phenylacetamido)-N-benzoyl-N,3,3-trimethyl-7-oxo-4-thia-1-azabicyc1o[3.2.0]heptane-2-carboxamideTriethylamine 1.01 g., 0.01 mole) is added to a mixture of6-(D-(-)-2-amino-2-phenylacetamido)-3,3- dimethyl-7-oxo-4-thia- 1-azabicyclo 3 .2 .0 heptane-2- carboxylic acid (3.49 g., 0.01 mole) andmethylene chloride (100 ml.), and the mixture is stirred threefourthshour at room temperature. Then N-methylbenzimidoyl chloride (1.54 g.,0.01 mole) is added all at once, and the mixture is reacted andworked-up in a manner similar to Example 1, giving a white solid 1.8 g.,39 percent), m.p. 102-121(uncorr.).

Analysis Calcd. for C24H25N404S:

C, 61.78; H, 5.61; N, 12.01. Found: C, 66.49; H, 6.35; N, 12.05.

EXAMPLE 5N-Benzoyl-6-(2,2-dimethy1-5-oxo-4-phenylimidazolidin-1-yl)-3,3-dimethyl-7-oxo-N-phenyl-4-thia-1-azabicyclo[3.2.0]heptane-Z-carboxamide6-(2,2-Dimethyl-5-oxo-4-phenylimidazolidin-1-yl)- 3,3-dimethyl27-oxo-4-thia-1 -azabicyclo[ 3.2.01heptane-Z-carboxylic acid(3.90 g., 0.01 mole) is added to anhydrous methylene chloride (100 ml.)followed by triethylamine (1.01 g., 0.01 mole), giving a solution. Thensolid N-phenylbenzimidoyl chloride (2.16 g., 0.01 mole) is added all atonce to the stirred solution, and the resulting solution is kept at roomtemperature for 2 hours. Then the solution is washed twice with coldwater, twice with cold 0.13 M/pl-l 7.4/(K HPO IKH PO buffer and driedthrough sodium sulfate. The resulting filtrate is dried over magnesiumsulfate, and then concentrated at 40 under vacuum, giving a white foam.The foam is dissolved in methylene chloride ml.) and anhydrous ether isadded to the cloud point 40 ml.). The solution is filtered and thefiltrate is stirred in a 250 ml. Erlenmeyer flask in an ice bath.Pentane (200 ml.) is added all at once, giving a white solid. The solidis rubbed with a glass rod and stirring is continued for about one-halfhour, until the solid becomes more crystalline. The mixture is filtered,giving a white solid (3.5 g., 62 percent), m.p. 108117 (uncorr.).

Analysis Calcd. for C H N O S:

C, 67.58; H, 5.67; N, 9.85; S, 5.64. Found: C, 66.98; H, 5.45; N, 8.38;S, 5.57.

EXAMPLE 6 N-Benzoyl-6-(2,2-dimethyl-5-oxo-4-phenylimidazolidinl -yl)-N,3,3-trimethyl-7-oxo-4-thia-1- 1. An antibiotic compound having theformula:

in which R and R are independently hydrogen or lower alkyl of one tofour carbon toms; a d R and R are members independently selected fromthe group consisting of a lower alkyl radical of one to four carbonatoms and the phenyl radical.

2. As a compound of claim 1; N-benzoyl-3,3-dimethyl-7-oxo-6-(2-phenoxyacetamido)-N-phenyl-4-thia-1-azabicyclo[3.2.0l-heptane-Z-carboxamide.

3. As a compound of claim 1; N-benzoyl-N,3,3-trimethyl-7-oxo-6-(2-phenoxyacetamido)-4-thia-1-azabicyclo[3.2.0heptane-2-carboxamide.

4. As a compound of claim 1; 6-(D-(-)-2-amino-2-phenylacetamido)-N-benzoyl-3,3-dimethyl-7-oxo-N-phenyl-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxamide.

5. As a compound of claim 1; 6-(D-(-)-2-amino-2-phenylacetamido)-N-benzoyl-N,3,3-trimethyl-7-oxo-4- thial-azabicyclo-[ 3.2.0 lheptane-Z-carboxamid.

6. As a compound of claim 1; N-benzoyl-6-(2,2- dimethyl-S-oxo-4-phenylimidazolidin- 1 -y1)-3 ,3- dimethyl-7-oxo-N-phenyl-4-thial-azabicyclo[ 3.2.0 heptane-Z-carboxamide.

7. As a compound of claim 1; N-benzoyl-6-(2,2-dimethyl-5-oxo-4-phenylimidazolidinl -yl )-N 3 ,3-trimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2- carboxamide.

PO-1O5O UNITED STATES PATENT OFFICE 4 CERTIFECATE 0F CORRECTKUN P n N55,692,774 Dated. September 19, 1972 Inventor) John H. Sellstedt andMilton Wolf It is certified that error appears in the above-identifiedpatent and that said Letters Patent are hereby corrected as shown below:

On the cover sheet, insert I [73] Assignee: American I Home ProductsCorporation, New York, NJ.

Column 5 line 2, after "dimethyl" delete "2" and insert a hyphen 1 7Column 6, Claim 3, line 3, after [3.2.0 insert a closing bracket Signedand sealed this 8th day of May 1973.

(SEAL) Attest:

EDWARD M.FLETCHER,JR. ROBERT GOTTSCHALK Attesting Officer Commissionerof Patents

2. As a compound of claim 1;N-benzoyl-3,3-dimethyl-7-oxo-6-(2-phenoxyacetamido)-N-phenyl-4-thia-1-azabicyclo(3.2.0)-heptane-2-carboxamide.
 3. As a compound of claim 1;N-benzoyl-N,3,3-trimethyl-7-oxo-6-(2-phenoxyacetamido)-4-thia-1-azabicyclo(3.2.0)heptane-2-carboxamide.
 4. As a compound of claim 1;6-(D-(-)-2-amino-2-phenylacetamido)-N-benzoyl-3,3-dimethyl-7-oxo-N-phenyl-4-thia-1-azabicyclo(3.2.0)heptane-2-carboxamide.
 5. As a coMpound ofclaim 1;6-(D-(-)-2-amino-2-phenylacetamido)-N-benzoyl-N,3,3-trimethyl-7-oxo-4-thia-1-azabicyclo-(3.2.0)heptane-2-carboxamide.6. As a compound of claim 1;N-benzoyl-6-(2,2-dimethyl-5-oxo-4-phenylimidazolidin-1-yl)-3,3-dimethyl-7-oxo-N-phenyl-4-thia-1-azabicyclo(3.2.0)heptane-2-carboxamide.
 7. As acompound of claim 1;N-benzoyl-6-(2,2-dimethyl-5-oxo-4-phenylimidazolidin-1-yl)-N,3,3-trimethyl-7-oxo-4-thia-1-azabicyclo(3.2.0)heptane-2-carboxamide.